Therapeutic agent for treatment and prevention of adult respiratory distress syndrome

Description

[0001] This invention describes a novel therapeutic agent and, more particularly, the use of 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl-L-valyl-L-proline 1(RS)-(1-trifluoroacetyl-2-methylpropyl)amide, or a pharmaceutically acceptable salt thereof, in the prevention or treatment of adult respiratory distress syndrome (hereinafter ARDS). (Although the therapeutic product is named here as 1(RS), the invention described herein includes any ratio of the 1(R)- and 1(S)-isomers of the above named compound, or the pharmaceutically acceptable salts thereof.)

[0002] ARDS is a major cause of morbidity (160,000-300,000 cases per year in the U.S.A.) and mortality (70-90% mortality) without effective therapy. ARDS is the final common pathway for a number of acute injuries, ranging from massive transfusion to neurological injury to sepsis. Lung injury is manifest as pulmonary edema, frequently hemorrhagic, with normal left-sided cardiac pressures (hence non-cardiogenic pulmonary edema). Current therapy consists of oxygen, antibiotics and supportive measures.

[0003] Neutrophil activation appears to be involved in the majority of cases of ARDS. There is evidence of elastolytic activity in secretions from ARDS patients. There is also neutrophil accumulation consistent with brisk chemotaxis and neutrophil activation. One hundred percent of patients who have undergone pulmonary thromboendarterectomy have developed ARDS localized to the re-perfused segment or lobe.

[0004] Accordingly, the present invention provides a novel therapeutic agent for use in the prophylactic or therapeutic treatment of ARDS in a mammal, especially a human, in need thereof which product comprises 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl-L-valyl-L-proline 1(RS)-(1-trifluoroacetyl-2-methylpropyl)amide, or a pharmaceutically acceptable salt thereof.

[0005] As a further aspect of the invention, there is provided the use of 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl-L-valyl-L-proline 1(RS)-(1-trifluoroacetyl-2-methylpropyl)amide, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylactic or therapeutic treatment of ARDS.

[0006] As another aspect of the invention, there is provided a method of prevention or treatment of ARDS in a mammal, especially a human, in need thereof with 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl-L-valyl-L-proline 1(RS)-(1-trifluoroacetyl-2-methylpropyl)amide, or a pharmaceutically acceptable salt thereof.

[0007] As yet another aspect of the invention, there is provided a method of prevention or treatment of ARDS with 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl-L-valyl-L-proline 1(RS)-(1-trifluoroacetyl-2-methylpropyl)amide, or a pharmaceutically acceptable salt thereof, in combination with one or more other agents indicated for the prevention or treatment of ARDS. Such agents include, but are not limited to, antibiotics, bronchodilators, corticosteroids, oxygen, mucolytics, and mucorheologic agents.

[0008] Suitable pharmaceutically acceptable salts of 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl-L-valyl-L-proline 1(RS)-(1-trifluoroacetyl-2-methylpropyl)amide (hereafter referred to as "the Compound") include, for example, those described in United States patent 4,910,190, for example, alkalai metal and alkaline earth metal salts (such as sodium, potassium, calcium or magnesium salts), ammonium salts, and salts with organic bases affording a pharmaceutically acceptable cation. A preferred salt of the Compound for use for prevention or treatment of ARDS is, for example, a sodium or potassium salt.

[0009] The Compound and its production are described in United States patent 4,910,190 where it was referred to as 3(RS)-[4-[(4-chlorophenyl)sulfonylaminocarbonyl]phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide, but the name given hereinabove is now preferred. It is noted that Dess-Martin periodinane, described as the preferred oxidant and used in the final step for the production of the Compound in Examples 104 and 121, may in certain circumstances constitute an explosive hazard. Accordingly, it may be preferred to use an alternative oxidant for preparing the ketone from the corresponding alcohol. Alternative methods which may be useful include the use of oxalyl chloride, dimethyl sulfoxide and a tertiary amine (with the best results being obtained with 10-20 equivalents of oxidizing agent); the use of acetic anhydride and dimethyl sulfoxide; the use of chromium trioxide pyridine complex in methylene chloride; and the use of alkaline potassium permanganate solution. For example, the Compound may be obtained from the corresponding alcohol in approximately 60% yield using two equivalents of the latter oxidant.

[0010] In use, the Compound will generally be administered for prophylactic or therapeutic treatment of ARDS in the form of a conventional pharmaceutical composition, for example, as generally described in United States patent 4,910,190, and preferably as an intravenous injection. A formulation providing a solution containing a concentration of 10 mg/mℓ of the Compound and suitable for use with a nebulizer or as an injectable solution is described below in Example 1. A suitable nebulizer for use is, for example, a RETEC (trademark) nebulizer, in which the solution is nebulized with compressed air.

[0011] In general, the therapeutic agent will be administered to humans at a daily dose in the range of, for example, 1 to 20 mg/kg (especially 5 to 7 mg/kg) of the Compound intravenously. However, it readily will be understood that it may be necessary to vary the dose of therapeutic product administered in accordance with well known medical practice to take account of the nature and severity of the ARDS under treatment, concurrent therapy, and the age, weight and sex of the patient receiving treatment. It similarly will be understood that generally equivalent amounts of a pharmaceutically acceptable salt of the Compound also may be used.

[0012] The utility of the Compound, or a pharmaceutically acceptable salt thereof, in the treatment of ARDS may be demonstrated in a therapeutic intervention trial, for example as described below in Study A, in which improvement in clinical or biochemical parameters may be measured. The utility of the Compound or a pharmaceutically acceptable salt thereof, in the prevention of ARDS may be demonstrated in a prophylactic trial using the therapeutic agent for prophylaxis in patients at risk for ARDS, for example as described below in Study B, in which clinical evidence of the occurrence of ARDS, as well as improvement in clinical and biochemical parameters may be measured.

[0013] Study A in ARDS is an interventional trial using a randomized, double blind, parallel study in 24 adult patients assigned to receive 5 to 7 mg/kg/day of the Compound or vehicle (placebo) to be administered by intravenous infusion for 7 to 14 days. A formulation as described in Example 1 may be used for the treatment group, and a similar formulation without the Compound for the vehicle (control) group. Clinical outcomes which are evaluated include mortality, pulmonary hemodynamics, and supplemental oxygen requirement. Physiological sequelae, such as on pulmonary hypertension and pulmonary mechanics also may be evaluated.

[0014] Study B in ARDS is a prophylactic trial using a randomized, double-blind, parallel study design to be conducted in 10-20 patients administered 5-7 mg/kg/day of the Compound or placebo intravenously for 3 to 4 days prior to pulmonary thromboendarterectomy. Dosing is continued for 3 days to 1 week postoperatively. Clinical outcomes which are evaluated include radiographic or pulmonary hemodynamic evidence of ARDS in re-perfused lobes. In this study, the patients act as their own controls (by use of the other, nonoperated lung) for physiological measurements or for bronchoalveolar lavage fluid for biochemical measurements, such as, for example protein leakage.

[0015] The following non-limiting Example illustrates a typical formulation of the Compound for use in the method of treatment provided by the invention.

Example 1

[0016] This example provides a formulation for 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl-L-valyl-L-proline 1(RS)-(1-trifluoroacetyl-2-methylpropyl)amide, listed as a THERAPEUTIC AGENT, which provides a strength of 10 mg/mℓ in phosphate-buffered saline and is suitable for a nebulizer solution or for an injectable solution. A corresponding PLACEBO formulation is also provided. The prepared solutions are preferably sealed in ampules of a convenient size, for example 5 mℓ, and stored with refrigeration until use.

INGREDIENT	WEIGHT PER mℓ
	10.0 mg	PLACEBO
THERAPEUTIC AGENT (1)	10.0 mg	--
Dibasic Sodium Phosphate, Heptahydrate, USP	11.97 mg	10.74 mg
Monobasic Sodium Phosphate, Monohydrate, USP	0.74 mg	1.25 mg
Sodium Chloride, USP	4.50 mg	5.48 mg
1 N Sodium Hydroxide Solution or 0.05 M Monobasic Sodium Phosphate Solution (2)	q.s.	q.s.
Water for Injection, USP q.s. ad	1.0 mℓ (1.01 gℓ)	1.0 mℓ (1.01 gℓ)

(1) The nominal concentration of THERAPEUTIC AGENT in this formulation is 10 mg/mL. A manufacturing adjustment is made for the drug substance purity.

(2) Added to adjust pH to 7.0-7.5

MANUFACTURING DIRECTIONS: THERAPEUTIC AGENT

[0017] 

1. Charge approximately 90% of the required amount of Water for Injection, USP to a vessel equipped with a suitable agitation device, and connected to a heater/cooler circulation bath.

2. Adjust the temperature of the circulation bath to 30 °C.

3. Charge with continuous stirring, the required amount of Dibasic Sodium Phosphate, Heptahydrate, USP and continue stirring until dissolved.

4. Charge very slowly with continuous stirring the required amount of THERAPEUTIC PRODUCT.

5. Continue to stir for approximately 30 minutes until dissolved, then decrease the temperature of the circulation bath to 25 °C.

6. Charge with continuous stirring the required amount of Monobasic Sodium Phosphate, Monohydrate, USP and continue stirring until dissolved.

7. Charge with continuous stirring the required amount of Sodium Chloride, USP and continue stirring until dissolved.

8. Measure the pH and adjust to 7.0 to 7.5 with 1 N Sodium Hydroxide Solution or 0.05 M Monobasic Sodium Phosphate Solution, if necessary.

9. Bring the batch to final weight (calculated from specific gravity of 1.01) with Water for Injection, USP.

10. Aseptically filter the bulk solution into a suitable, sterilized filling vessel. Aseptically fill and seal the ampules.

11. Leak test ampules and visually inspect for particulate matter and other defects.

MANUFACTURING DIRECTIONS: PLACEBO

[0018] The procedure listed above is carried out with the omission of steps 2, 4 and 5, and without the need for temperature control.

Claims

1. The use of 4-(4-chlorophenylsulphonylcarbamoyl)benzoyl-L-valyl-L-proline 1(RS)-(1-trifluoroacetyl-2-methylpropyl)amide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of adult respiratory distress syndrome.

2. The use as claimed in claim 1 wherein the pharmaceutically acceptable salt of the acid is selected from alkali metal and alkaline earth metal salts, ammonium salts, and salts with organic bases affording a pharmaceutically acceptable cation.

3. The use as claimed in claim 1 or 2 wherein the pharmaceutically acceptable salt of the acid is a sodium or potassium salt.

4. The use as claimed in claim 1, 2 or 3 where in addition another pharmacological agent indicated for the treatment of adult respiratory distress syndrome is used in the manufacture of the medicament.

5. The use as claimed in claim 4 wherein the other pharmacological agent is selected from antibiotics, bronchodilators, corticosteroids, oxygen, mucolytics and mucorheologic agents.

6. The use as claimed in any preceding claim wherein the medicament is in the form of an injectable solution.

Ansprüche

1. Verwendung von 4-(4-Chlorphenylsulfonylcarbamoyl)benzoyl-L-valyl-L-prolin-1(RS)-(1-trifluoracetyl-2-methylpropyl)amid oder eines pharmazeutisch verträglichen Salzes davon bei der Herstellung eines Arzneimittels zur Verwendung bei der Behandlung der akuten respiratorischen Insuffizienz.

2. Verwendung nach Anspruch 1, wobei das pharmazeutisch verträgliche Salz der Säure aus Alkalimetall- und Erdalkalimetallsalzen, Ammoniumsalzen und Salzen mit organischen Basen, die ein pharmazeutisch verträgliches Kation ergeben, ausgewählt ist.

3. Verwendung nach Anspruch 1 oder 2, wobei das pharmazeutisch verträgliche Salz der Säure ein Natrium- oder Kaliumsalz ist.

4. Verwendung nach Anspruch 1, 2 oder 3, wobei bei der Herstellung des Arzneimittels zusätzlich ein weiteres pharmakologisches Mittel, das zur Behandlung der akuten respiratorischen Insuffizienz indiziert ist, verwendet wird.

5. Verwendung nach Anspruch 4, wobei das weitere pharmakologisches Mittel aus Antibiotika, Bronchodilatatoren, Cortikosteroiden, Sauerstoff, Mukolytika und mukorheologischen Mitteln ausgewählt ist.

6. Verwendung nach einem der vorstehenden Ansprüche, wobei das Arzneimittel in Form einer injizierbaren Lösung vorliegt.

Revendications

1. Utilisation du 1(RS)-( 1-trifluoroacétyl-2-méthylpropyl)amide de 4-(4-chlorophénynylsulfonylcarbamoyl)-benzoyl-L-valyl-L-proline ou d'un sel de celui-ci acceptable du point de vue pharmaceutique dans la fabrication d'un médicament utile dans le traitement du syndrome de détresse respiratoire chez l'adulte.

2. Utilisation suivant la revendication 1 dans lequel le sel acceptable du point de vue pharmaceutique de l'acide est choisi parmi des sels de métaux alcalins et des sels de métaux alcaloino terteux, des sels d'ammonium et des sels formés avec des bases organiques fournissant un cation acceptable du point de vue pharmaceutique.

3. Utilisation suivant les revendication 1 ou 2, dans laquelle le sel acceptable du point de vue pharmaceutique de l'acide est un sel de sodium ou de potassium.

4. Utilisation suivit les revendications 1, 2 ou 3, dans laquelle il est utilisé de plus un autre agent pharmacologique indiqué pour le traitement du syndrome de détresse respiratoire chez l'adulte dans la fabrication du médicament.

5. Utilisation suivant la revendication 4, dis laquelle l'autre agent pharmacologique est choisi parmi des antibiotiques, des bronchodilatateurs, des corticostéroïdes, de l'oxygène des mycolytiques et des agents mucorhéologiques.

6. Utilisation suivant l'une quelconque des revendications précédentes, dans laquelle le médicament est sous la forme d'une solution injectable.